Agouti Antagonism of Melanocortin-4 Receptor: Greater Effect with Desacetyl-Alpha-melanocyte-stimulating Hormone (MSH) Than with Alpha-Msh.

Desacetyl-α-MSH is more abundant than α-MSH in the brain, the fetus, human blood, and amniotic fluid, but there is little information on its ability to interact with melanocortin receptors. The aim of this study is to compare and contrast the ability of desacetyl-α-MSH andα -MSH to couple melanocortin receptors stably expressed in HEK293 cells, to the protein kinase A (PKA) signaling pathway. Desacetyl-α-MSH activated mouse MC1, MC3, MC4 and MC5 receptors with EC50s = 0.13, 0.96, 0.53, and 0.84 nm, andα -MSH activated these receptors with EC50s = 0.17, 0.88, 1.05, and 1.34 nm, respectively. Mouse agouti protein competitively antagonized α-MSH and desacetyl-α-MSH coupling to the MC1-R similarly. In contrast, mouse agouti protein antagonized desacetyl-α-MSH much more effectively and potently than α-MSH coupling the MC4-R to the PKA signaling pathway. Furthermore, mouse agouti protein (10 nm) significantly reduced (1.4-fold) the maximum response of mMC4-R to desacetyl-α-MSH and 100 nm mouse agouti significantly increased (4.8-fold) the EC50. Minimal antagonism of α-MSH coupling mMC4-R to the PKA signaling pathway was observed with 10 nm mouse agouti, whereas both 50 and 100 nm mouse agouti appeared to reduce the maximum reponse (1.1- and 1.3-fold, respectively) and increase the EC50 (2.5- and 3.4-fold respectively). Mouse agouti protein did not significantly antagonize either α-MSH or desacetyl-α-MSH coupling mouse MC3 and MC5 receptors. Understanding the similarities and differences in activation of melanocortin receptors by desacetyl-α-MSH and α-MSH will contribute to delineating the functional roles for these endogenous melanocortin peptides.